Metabolic-associated fatty liver disease and hepatocellular carcinoma: a prospective study of characteristics and response to therapy.

BACKGROUND AND AIM: The rising incidence of hepatocellular carcinoma (HCC) in Australia is related to increasing rates of metabolic-associated fatty liver disease (MAFLD). This study aimed to prospectively characterize the metabolic profile, lifestyle, biometric features, and response to treatment of HCC patients in an Australian population. METHOD: Multicenter prospective cohort analysis of newly diagnosed HCC patients at six multidisciplinary team meetings over a 2-year period. RESULTS: Three hundred and thirteen (313) newly diagnosed HCC patients with MAFLD (n = 77), MAFLD plus other liver disease (n = 57) (the "mixed" group), and non-MAFLD (n = 179) were included in the study. Alcohol-associated liver disease (ALD) (43%) and MAFLD (43%) were the most common underlying liver diseases. MAFLD-HCC patients were older (73 years vs 67 years vs 63 years), more likely to be female (40% vs 14% vs 20%), less likely to have cirrhosis (69% vs 88% vs 85%), showed higher ECOG, and were less likely to be identified by screening (29% vs 53% vs 45%). Metabolic syndrome was more prevalent in the MAFLD and mixed groups. The severity of underlying liver disease and HCC characteristics were the same across groups. While the MAFLD population self-reported more sedentary lifestyles, reported dietary patterns were no different across the groups. Dyslipidemia was associated with tumor size, and those taking statins had a lower recurrence rate. CONCLUSION: Equal to ALD, MAFLD is now the most common underlying liver disease seen in HCC patients in Australia. Future HCC prevention screening and treatment strategies need to take this important group of patients into consideration.

Early viral-specific T-cell testing predicts late cytomegalovirus reactivation following liver transplantation.

INTRODUCTION: Although antiviral prophylaxis is effective in preventing early cytomegalovirus (CMV) reactivation following liver transplantation (OLT), it predisposes patients to late CMV after prophylaxis has ceased. QuantiFERON-CMV (QFN-CMV, Qiagen, The Netherlands) measures an individual's viral-specific immune response. METHODS: Fifty-nine OLT recipients were prospectively monitored post-OLT in an observational cohort study. QFN-CMV was performed at regular time-points. An absolute QFN-CMV <0.1 IU/mL was considered non-reactive. RESULTS: 50/59 (84.7%) had a reactive QFN-CMV by M6. 38/59 (64.4%) had antiviral prophylaxis or treatment before M6, with 31/38 (81.6%) developing a reactive QFN-CMV by 6 months. Over 90% already had a reactive result as early as 3 months post transplant, 3 patients (5.08%) developed late CMV between 6-12 months (median 251 days)-all had a non-reactive M6 QFN-CMV. And 2/3 experienced CMV disease. Non-reactive M6 QFN-CMV was significantly associated with late CMV (OR = 54.4, PPV = 0.33, NPV = 1.00, P = .003). CONCLUSION: Although only 5% of recipients developed late CMV, 2/3 suffered CMV disease. M6 QFN-CMV has an excellent NPV for late CMV, suggesting patients who exhibit a robust ex vivo immune response at M6 can safely cease CMV monitoring. Furthermore, >90% already express viral-specific immunity as early as 3 months. Conceivably, antiviral prophylaxis could be discontinued early in these patients.

Liver transplantation for the treatment of homozygous familial hypercholesterolaemia in an era of emerging lipid-lowering therapies.

Homozygous familial hypercholesterolaemia (FH) causes severe premature coronary artery disease because of very high levels of low density lipoprotein (LDL)-cholesterol. Standard lipid-lowering drugs and LDL-apheresis may not be sufficiently effective. Liver transplantation replaces defective LDL receptors and vastly improves the lipid profile, and we present the first report of an Australian adult to receive this treatment. Emerging drug treatments for FH may be alternatives to LDL-apheresis and transplantation, but long-term safety and efficacy data are lacking for all of these options.

Evidence for association of an interleukin 23 receptor variant independent of the R381Q variant with rheumatoid arthritis.

OBJECTIVE: The rare allele of a non-synonymous interleukin 23 receptor (IL23R) single nucleotide polymorphism (SNP) rs11209026 (p.Arg381Gln) confers strong protection against Crohn disease (CD) and psoriasis. Other IL23R variants also exhibit association with CD, genetically independent of rs11209026. In rheumatoid arthritis (RA), IL23 is an important determinant of the production of IL17A, a cytokine of consequence in inflammation and bone destruction. While there is no previous support for strong association of IL23R with RA, the possibility of a weaker role for IL23R variants in the aetiology of RA cannot be eliminated. METHODS: A New Zealand RA cohort was tested for association with six IL23R SNPs and the resulting data combined with a reanalysis of the Wellcome Trust Case Control Consortium data and a previously published Spanish data set. The combined data set totals over 3000 Caucasian cases and 3800 controls, which has sufficient power to detect a risk of as low as odds ratio (OR) = 1.2. RESULTS: Our data emphasise the lack of association of rs11209026 with RA (OR 1.01, 95% confidence interval (CI) 0.88 to 1.16, p = 0.86). However there was some evidence for association of rs1343151 with RA (OR 1.14, 95% CI 1.06 to 1.22, p = <0.001). CONCLUSIONS: While requiring further replication, these data further support a role for the IL17A/IL23 pathway in RA. Understanding how different variants of IL23R associate, at varying levels of strength, with contrasting groups of immune-mediated diseases (CD, psoriasis, ankylosing spondylitis, RA) will enhance knowledge on the aetiology of these diseases.

Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis.

OBJECTIVE: There is increasing evidence that gene copy-number variation influences phenotypic variation. Chemokine ligand 3-like 1 (CCL3L1) is encoded by a variable copy-number gene, and binds to several pro-inflammatory cytokine receptors, including chemokine receptor 5 (CCR5). Considering lymphocyte recruitment by beta-chemokines is a feature of autoimmunity, and that the CCR5Delta32 variant is associated with protection to rheumatoid arthritis (RA), we hypothesised that CCL3L1 copy-number influences susceptibility to RA and type 1 diabetes (T1D). METHODS: We measured CCL3L1 copy-number in 1136 RA cases from New Zealand (NZ) and the UK, 252 NZ T1D cases and a total of 1470 controls. All subjects were ancestrally Caucasian. RESULTS: A copy-number higher than 2 (the most common copy number) was a risk factor for RA in the NZ cohort (odds ratio (OR) 1.34, 95% CI 1.08-1.66, p = 0.009) but not the smaller UK RA cohort (OR 1.09, 95% CI 0.75-1.60, p = 0.643). There was evidence for association in the T1D cohort (OR 1.46, 95% CI 0.98-2.20, p = 0.064) and in the combined RA/T1D cohort (OR 1.30, 95% CI 1.00-1.54, p = 0.003). Genetic interaction between CCL3L1 dosage and CCR5 genotype was found; the increased genetic risk conferred by higher CCL3L1 copy-number was ablated by a dysfunctional CCR5 (CCR5Delta32). CONCLUSIONS: These data suggest that increased CCL3L1 expression may enhance inflammatory responses and increase the chance of autoimmune disease. Genetic interaction data were consistent with a biologically plausible model; CCR5Delta32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.

Review article: sarcopenia in cirrhosis--aetiology, implications and potential therapeutic interventions.

BACKGROUND: Sarcopenia (loss of muscle mass) is common in cirrhosis and is associated with poor outcomes. Current teaching recommends the use of protein supplementation and exercise, however, this fails to address many other factors which contribute to muscle loss in this setting. AIMS: To summarise existing knowledge regarding the aetiology of sarcopenia in cirrhosis, diagnostic modalities and the clinical significance of this condition. In addition to discuss recent research findings that may allow the development of more effective treatments. METHODS: We conducted a Medline and PubMed search using the search terms 'sarcopenia', 'muscle', 'body composition', 'cirrhosis', 'liver' and 'malnutrition' from inception to October 2015. RESULTS: Cirrhotic patients with sarcopenia have reduced survival, experience increased rates of infection and have worse outcomes following liver transplantation. The aetiology of this condition is more complex than simple protein and calorie malnutrition. Cirrhosis also results in depleted glycogen stores and metabolic alterations that cause excessive protein catabolism, increased activation of the ubiquitin-proteasome pathway and inappropriate muscle autophagy. Satellite cell differentiation and proliferation is also reduced due to a combination of elevated myostatin levels, reduced IGF-1 and hypogonadism. Although there is some evidence supporting the use of late evening snacks, branched chain amino acid supplementation and high protein/high calorie diets, well designed clinical trials addressing the effects of treatment on body composition in cirrhosis are lacking. CONCLUSION: Sarcopenia in cirrhosis has a complex pathogenesis and simple dietary interventions are insufficient. Improved understanding of the multiple mechanisms involved should allow the development of more effective therapies, which target the specific underlying metabolic derangements.

De novo hepatitis B infection acquired during liver transplantation.

Although the use of donor organs from patients negative for hepatitis B surface antigen (HBsAg) but positive for hepatitis B core antibody (HBcAb) is well known to have the potential to transmit hepatitis B to the recipient, routine screening of organ donors for HBcAb is not yet implemented in the UK. We investigated whether current organ donor screening for hepatitis B infection is effective in preventing de novo hepatitis B infection after liver transplantation. The database of the liver transplant unit at the Queen Elizabeth Hospital, Birmingham, was searched for all cases of de novo hepatitis B after liver transplantation between January 1982 and July 2000. Four cases were identified from a population of 1354 (0.3%) adult liver transplant recipients. In all cases, the likely source of hepatitis B in the recipient was the donated organ. De novo acquisition of hepatitis B after liver transplantation occurs within the UK. This problem is likely to be resolved by the institution of HBcAb testing in all liver donors. Continuing the current practice in the UK of incomplete donor hepatitis B testing (HBsAg serology only) can no longer be justified. De novo acquired infection has potentially life-threatening implications to the liver recipient and their contacts.

A multi-centre study of piroxicam in the treatment of osteoarthritis and rheumatoid arthritis in general practice.

An open, multi-centre, non-comparative study was carried out in general practice to assess the efficacy and tolerance of piroxicam in 159 patients with osteoarthritis and 27 patients with rheumatoid arthritis. Initial dosage ranged from 10 to 40 mg piroxicam and all but a few patients continued treatment with 20 mg once daily. Mean duration of treatment was 47.5 days in the osteoarthritis group and 38.4 days in the rheumatoid arthritis group. Marked or moderate improvement was reported at the final visit by 68.6% and 87.7% of osteoarthritis and rheumatoid arthritis patients, respectively. The attending physician's assessment of efficacy indicated an excellent or moderate response in 89.3% of osteoarthritis patients and 84.7% of rheumatoid arthritis patients, with 71.2% of the former and 51.9% of the latter patients preferring piroxicam to the medication which was taken prior to the onset of the study. Highly significant numbers in each group reported an improvement in all parameters of disease activity. Side-effects, predominantly gastro-intestinal, were reported in 54 patients, but cessation of medication was required in only 14 patients.

The functional significance of sacroiliitis and ankylosing spondylitis in Reiter's syndrome.

The frequent development of sacroiliitis and ankylosing spondylitis (AS) in patients suffering from Reiter's Syndrome (RS) has been stressed by a number of authors. This study was designed to ascertain the frequency of these problems in our RS patients, whether they were related to other clinical features of RS and what was the extent of the resulting disability. Fifty-five patients (50 men and 5 women) with RS with a mean duration of 9.3 years were assessed radiologically to determine the prevalence of sacroiliitis and thoracolumbar syndesmophyte formation. These radiological findings were correlated with HLA-B27, clinical features and functional status. Sacroiliitis was found in 22 patients (40%) but was mild in severity, frequently asymmetrical and very rarely associated with syndesmophyte formation. Sacroiliitis occurred significantly more commonly in patients with iritis and/or a prolonged disease duration (p less than 0.05) but although it was also found more frequently in HLA-B27 positive patients this was not significant (0.1 greater than p greater than 0.05). Some restriction in back movement was observed in 31 patients (56.3%) but only two patients satisfied New York criteria for AS and just one was functionally impaired by his back disease. Although the frequent finding of sacroiliitis in RS may provide an interesting insight into the interrelationship between RS and AS, our study shows that this sacroiliitis is commonly asymptomatic and does not provide a problem in management.

Simultaneous occurrence of focal nodular hyperplasia and primary sclerosing cholangitis in a young female.

We report the case of a 22-year-old female with primary sclerosing cholangitis who was found, during hepatic imaging, to have a large liver mass. Imaging techniques and histological examination confirmed the mass to be focal nodular hyperplasia. A review of the literature indicates that the simultaneous occurrence of these two hepatic pathologies is unique. The differential diagnosis of hepatic masses in primary sclerosing cholangitis is discussed. Focal nodular hyperplasia needs to be included in the differential diagnosis of hepatic lesions in primary sclerosing cholangitis.

Conjugation of para-nitrophenol by the isolated perfused neonatal sheep liver.

We examined the metabolism of para-nitrophenol (PNP) in the isolated perfused neonatal sheep liver (n = 8, 0.25-11 days) and compared the findings with our previous data from the perfused near-term fetal sheep liver (Ring, J. A., et al. Drug Metab Dispos 1996, 24, 1378). A three-step dosage regimen was used (72, 144, and 288 micromol of PNP). At the end of each dosage phase, PNP had fallen below detectable levels, and 101 +/- 16% of the dose was accounted for as PNP conjugates. Elimination of PNP from perfusate varied with dose. Elimination was first order with the 72-micromol dose; with the 144-micromol dose, elimination was first order in four livers but Michaelis-Menten kinetics in the remaining four. With all the 288-micromol doses, elimination was Michaelis-Menten and gave the following biochemical parameters: K(m) = 255 +/- 138 microM (fetal = 14.7 microM, P < 0.01), V(max) = 515 +/- 285 nmol/min/g liver (fetal = 34.3 nmol/min/g liver, P < 0.01), and intrinsic hepatic clearance = 2.36 +/- 1.21 mL/min/g liver (fetal = 4.74 mL/min/g liver, P > 0. 05). The mean shunt-corrected hepatic extraction ratio of PNP was 0. 82 (range, 0.40-1.0) and strongly correlated with neonatal age (r = 0.90, P < 0.05). We conclude that PNP is highly extracted by the isolated perfused neonatal sheep liver at much higher efficiency than in the near-term fetal sheep, reflecting a maturation of conjugation that progresses further in the early neonatal period.

Neonatal hepatic propranolol elimination: studies in the isolated perfused neonatal sheep liver.

Using the isolated perfused neonatal sheep liver model, we examined the disposition of propranolol (n = 8, age 0.25-10 days) and compared our findings with our previous study from the perfused near-term fetal sheep liver (Ring JA, et al. 1995. Drug Metab Dispos 23:190-196). Within 45 min of dosage, perfusate propranolol levels had fallen by three orders of magnitude to be less than the limit of detection. Perfusate disappearance curves were monoexponential in six experiments and biexponential in two experiments. The mean shunt-corrected hepatic extraction ratio was 0.92 +/- 0.09, much greater than that seen in the fetal sheep liver (0.26 +/- 0.13, P < 0.0001) but still less than values in the adult sheep (0.97). At the conclusion of the perfusion, 4-hydroxypropranolol was the major metabolite present and 5-hydroxypropranolol and N-desisopropylpropranolol were minor metabolites. We conclude that the isolated perfused neonatal sheep liver is a useful model with which to study the maturation of neonatal hepatic drug oxidation. Our study shows that propranolol is rapidly eliminated by the neonatal liver to form several metabolites at rates far greater than in the fetal liver, but rates of elimination have not yet reached that reported in the adult sheep liver.

Uptake and excretion of sodium taurocholate by the isolated perfused neonatal sheep liver.

We present a model for perfusion of the isolated perfused neonatal sheep liver which allows examination of drug disposition by the intact organ. We studied the disposition of sodium taurocholate (TC) in seven neonatal lambs (ages 2-11 days) and compared the results with earlier data from the perfused fetal sheep liver (Ring, J. A. et al. Biochem. Pharmacol. 1994, 48, 667-674). Measurements of perfusion pressure, oxygen consumption, lactate:pyruvate ratio, bile flow, and liver histology indicated that the preparation was both viable and stable over a 2 h period. [14C]-labeled TC was added to the reservoir by constant infusion (30 micromol/h) and the ductus venosus shunt quantitated by injection of [153Gd]-labeled microspheres. Shunt-corrected hepatic extraction ratio of TC was 0. 56 +/- 0.14 (fetal 0.23 +/- 0.16, p < 0.005) and clearance of TC was 0.92 +/- 0.35 mL/min/g liver (fetal 0.44 +/- 0.23 mL/min/g, p < 0. 01). We conclude that the isolated perfused neonatal sheep liver is a useful experimental model which will facilitate the study of the developmental physiology and pharmacology of the liver. There is considerable maturation of the biliary excretion of TC between the late fetal and early neonatal periods in the lamb.

Revealing the cause of cryptogenic cirrhosis by posttransplant liver biopsy.

INTRODUCTION: Because of the tendency for preexisting diseases to recur following liver transplantation, studying the course of patients who were transplanted for their cryptogenic cirrhosis may reveal features of the original cause. We examined the clinicopathological posttransplant progression of patients transplanted due to cryptogenic cirrhosis with emphasis on the detection of posttransplant steatosis and steatohepatitis. METHODS: The data on all patients transplanted for cryptogenic cirrhosis and their routine 1-year posttransplant liver biopsies were compared to a control group of a randomized sample of patients transplanted for other indications matched for length of follow-up. The posttransplant histological diagnosis was based on the latest available biopsy. RESULTS: Among 1710 patients, 39 present with cryptogenic etiology survived at least 1 year after transplantation. The control group consisted of 78 patients. The mean ages of the two groups were 50.7 and 49.3 years and the mean follow-up periods 6.2 and 5.7 years, both of which were similar. There was a significantly greater prevalence of posttransplant steatosis and steatohepatitis among the cryptogenic group (37.5 vs 16.7%, P = .048). The difference in patients with at least moderate steatosis was more pronounced (18.8 vs 3.3%, P = .035). Half of these cases progressed to fibrosis and cirrhosis after 48 months. CONCLUSIONS: This study found a greater incidence of allograft steatosis and steatohepatitis among patients transplanted for cryptogenic cirrhosis compared with a control group. A significant proportion of these patients developed a picture resembling nonalcoholic steatohepatitis, which progressed to fibrosis and cirrhosis.

Variation in ANA titres in Auckland.

AIM: To determine the intralaboratory and interlaboratory variation in reported ANA titres in three Auckland laboratories, and to see if this has improved since a similar study was performed in 1981. METHODS: Serum samples on 26 subjects with rheumatological symptoms were sent to the three laboratories on two separate days in 1993, and the presence and titre of ANA determined. RESULTS: The number of titre dilutions by which duplicate samples differed within each laboratory has decreased since the previous study, and variation within each laboratory of greater than two dilutions was not observed. The correlation between the laboratories has improved since the previous study, particularly for Lab A vs. Lab B. CONCLUSION: The ANA test, as expressed in titres, is more reproducible in Auckland laboratories than has been the case in the past.

The arthritic ulcer: a retrospective study of peptic ulceration in patients with rheumatoid arthritis.

Four patients with duodenal ulcer (DU) and nine with gastric ulcer (GU) were admitted to a general hospital rheumatology ward over an eighteen month period. Indigestion was the predominant though not invariable presenting symptom. Most ulcers healed with cimetidine over a period of six weeks to eight months, though two patients required surgery. Non-steroidal anti-inflammatory drugs were continued in all patients without major complications. Unanswered questions raised by the study, to which a prospective trial could be directed, include the sensitivity and specificity of indigestion as a presenting feature of peptic ulceration, the effect of non-steroidal anti-inflammatory drugs (NSAID's) other than aspirin on the aetiology and natural history of gastric ulceration, and the rational choice of antirheumatic and anti-ulcer therapy in rheumatoid patient in whom peptic ulceration has occurred.

Synovial fluid lactic acid in septic arthritis.

Lactic acid concentrations in the synovial fluid of 71 patients with inflammatory arthritis were determined by an enzyme method. In 63 samples from 54 patients with a variety of non-septic arthritides, including rheumatoid arthritis, reactive arthritis and gout, the concentration of lactic acid was never greater than 10.2 mmol/l, whereas all twelve patients with septic arthritis had concentrations of 11 mmol/l or greater. Two patients with gonococcal arthritis did not have raised lactic acid concentrations. The enzyme method of lactic acid estimation is an accurate reproducible means of differentiating septic from nonseptic arthritis prior to the isolation of the infecting organism. However, caution is necessary when interpreting the results in those patients who have recently received antibiotic therapy, or in whom gonococcal arthritis is suspected.

Use of the HLA B27 test in Auckland.

An assessment was made of the probability of HLA B27 associated disease in 74 patients who had recently been tested. Six patients had definite, 31 possible, and 37 very unlikely HLA B27 associated disease. Thirteen patients were HLA B27 positive. Fourteen tests were ordered by rheumatologists (43% HLA B27 + ve) and 60 by other doctors (12% HLA B27 + ve) p less than 0.01. Non-rheumatologists ordered an excessive number of tests in patients with a low probability of HLA B27 associated disease.

A survey of current prescribing practices of antiinflammatory and urate-lowering drugs in gouty arthritis.

OBJECTIVE: to assess the prescribing habits in late 1988 of rheumatologists (NZR) and a random sample of general practitioners (NZGP) managing gout and hyperuricaemia. DESIGN: self administered questionnaires containing two demographic questions and 24 items probing the selection and prescription of antirheumatic drugs in patients with acute gout, chronic tophaceous gout and asymptomatic hyperuricaemia were sent to every rheumatologist and a 10% random sample of general practitioners in active practice. RESULTS: replies were received from 26 of 27 (96%) rheumatologists and 163 of 207 (79%) of general practitioners Rheumatologists were more likely to use indomethacin as the preferred drug for acute gout, and colchicine either alone or as adjunctive therapy for prophylaxis in chronic gout to prevent acute attacks occurring following the introduction of urate lowering agents, although nonsteroidal antiinflammatory drugs (NSAIDs) were more commonly used for this purpose by both groups. Prior to prescribing urate lowering therapy general practitioners were more likely to attempt control of alcohol intake, and rheumatologists more likely to avoid concomitant low dose salicylates. Allopurinol was the preferred hypouricaemic drug, with rheumatologists more likely to prescribe an initial dose of 100 mg daily, and gradually increase the dose according to the serum urate (SeUa). Although a minority of respondents prescribed allopurinol for asymptomatic hyperuricaemia, general practitioners were more likely to do so at a lower level of serum urate. CONCLUSION: there was a high level of adherence to what is considered optimal contemporary practice, with a number of differences in prescribing habits probably reflecting differences in case selection between patients attending rheumatologists and general practitioners. The data indicates a continuing need for education programmes for both specialists and general practitioners.